Use of carboxamides for the treatment of tinnitus

ABSTRACT

The present invention relates to the use of carbamazepine derivatives in treating tinnitus.

The present invention relates to new pharmaceutical uses ofcarbamazepine derivatives.

More particularly the present invention relates to new pharmaceuticaluses of the carbamazepine derivatives of formula I

wherein

-   (a) R₁ represents hydrogen, and R₂ represents hydroxy or C₁-C₃alkyl    carbonyloxy, or-   (b) R₁ and R₂ together represent an oxo group,    and of their pharmaceutically acceptable salts.

The preparation of the compound of formula I wherein R₁ is hydrogen andR₂ represents hydroxy and of its pharmaceutically acceptable salts isdescribed, e.g., in U.S. Pat. No. 3,637,661. Such compound,monohydroxycarbamazepine, (10-hydroxy-10,11-dihydro-carbamazepine), themain metabolite of the antiepileptic oxcarbazepine (Trileptal®) is wellknown from the literature [see for example Schuetz H. et al.,Xenobiotica (GB), 16(8), 769-778 (1986)]. The compound is indicated tobe suitable for the treatment of psychosomatic disturbances, epilepsy,trigeminal neuralgia and cerebral spasticity.

The preparation of the compound of formula I wherein R₁ is hydrogen andR₂ represents C₁-C₃alkyl carbonyloxy and of the pharmaceuticallyacceptable salts thereof is described, e.g., in U.S. Pat. No. 5,753,646.The compounds are described to be efficacious against epilepsy.

The carbamazepine derivatives of formula I wherein R₁ representshydrogen, and R₂ represents hydroxy or C₁-C₃alkyl carbonyloxy constitutechiral compounds. For the purposes of the present invention, the chiralcompounds disclosed herein can be employed in the form of racemates, inmixtures comprising one enantiomer in excess (e.g., moreS-10-hydroxy-10,11-dihydro-carbamazepine thanR-10-hydroxy-10,11-dihydro-carbamazepine) or in enantiomerically pureform (e.g. pure S-10-hydroxy-10,11-dihydro-carbamazepine or pureS-10-acetoxy-10,11-dihydro-carbamazepine).

The compound of formula I wherein R₁ and R₂ together represent an oxogroup is known as oxcarbazepine(10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, marketed e.g.under the brand name Trileptal®). Oxcarbazepine is a knownanticonvulsant drug useful in the treatment of seizures of, for example,epileptic origin. Its preparation is described, e.g., in the Germanpatent 2,011,087.

Tinnitus is the medical term for roaring, buzzing, clicking, whistling,hissing, or high pitched ringing in the ears or inside the head.Tinnitus may be constant or occur intermittently in one or both ears.Although there are many theories about how tinnitus occurs, there is noscientific consensus to its origin. Some causes of tinnitus result froma blow to the head, large doses of aspirin, anemia, noise exposure,stress, impacted wax, hypertension and certain types of medications andtumors.

The term “other inner ear/cochlear excitability related diseases” asused herein includes, but is not restricted to neuronal loss, hearingloss, sudden deafness, vertigo or Meniere's disease.

In accordance with the present invention, it has now surprisingly beenfound that the compounds of formula I in free base or acid addition saltform is useful in the prevention and treatment of tinnitus and otherinner ear/cochlear excitability related diseases.

Hence, the present invention relates to the use of a compound of formulaI wherein

-   (a) R₁ represents hydrogen, and R₂ represents hydroxy or C₁-C₃alkyl    carbonyloxy, or-   (b) R₁ and R₂ together represent an oxo group,    or pharmaceutically acceptable salts thereof for the treatment of    tinnitus or other inner ear/cochlear excitability related diseases.

In one preferred embodiment of the present invention, R₁ representshydrogen and R₂ represent hydroxy.

In another preferred embodiment of the present invention, R₁ representshydrogen and R₂ represents acetoxy.

In a further preferred embodiment of the present invention, R₁ and R₂together represent an oxo group.

The activity in tinnitus of the compounds can be shown in standardtests, e.g. in the salicylate-induced tinnitus model in rats, or intinnitus models in cats, and in particular in those models describedherein.

It has been demonstrated [C. A. Bauer et al., Hearing Research 147(2000) 175-182] that chronic salicylate exposure causes upregulation ofglutamic acid decarboxylase (GAD) expression in the rat inferiorcolliculus (IC), associated with the development of tinnitus.Furthermore, electrophysiological recordings from auditory neurons usingpatch clamp recording techniques [D. Peruzzi et al. Neuroscience 101(2000) 403-416, X. Lin et al., Journal of Neurophysiology 79 (1998)2503-2512] and single neuron recordings [J. J. Eggermont and M.Kenmochi, Hearing Research 117 (1998) 149-160] showed that theexcitability of neurons is changed following salicylate and quininetreatment.

Administration of salicylate or quinine caused an increase in the firingrate auditory neurons measured by extracellular electrophysiologicalrecording techniques. Using in vitro electrophysiological recordingtechniques superfusion with salicylate increases the excitability of therecorded neurons. On administration of the compounds at concentrationsof about 1 nM to 300 μM, the effects of salicylate were reversed.

The pharmacological activity of the compounds of formula I may, forexample, also be evidenced in clinical studies known as such. Suchclinical studies are preferably randomized, double-blind, clinicalstudies in patients with tinnitus. The beneficial effects on tinnituscan be determined, e.g., directly through the results of these studies.

For the treatment of tinnitus and the other conditions mentioned herein,appropriate dosage will of course vary depending upon, for example, thespecific compound of formula I employed, the host, the mode ofadministration and the nature and severity of the condition beingtreated. However, in general, satisfactory results in animals areindicated to be obtained at a daily dosage of from about 1 to about 300mg/kg animal body weight. In larger mammals, for example humans, anindicated daily dosage is in the range from about 10 to about 3000 mg ofa compound of formula I, conveniently administered, for example, individed doses up to four times a day.

The compounds of formula I may be administered in any usual manner, e.g.orally, for example in the form of tablets or capsules, or parenterally,for example in the form of injection solutions or suspensions.

The present invention also provides pharmaceutical compositionscomprising a compound of formula I in association with at last onepharmaceutical carrier or diluent for use in the treatment of tinnitus.Such compositions may be manufactured in conventional manner.

Unit dosage forms may contain for example from about 2.5 mg to about1000 mg of a compound of formula I.

The invention further provides the use of a compound of formula I forthe manufacture of a pharmaceutical composition for the treatment oftinnitus and other inner ear/cochlear excitability related diseases suchas neuronal loss, hearing loss, sudden deafness, vertigo or Meniere'sdisease.

The invention further provides a method for the treatment of tinnitusand other inner ear/cochlear excitability related diseases such asneuronal loss, hearing loss, sudden deafness, vertigo or Meniere'sdisease in a subject in need of such treatment, which comprisesadministering to said subject a therapeutically effective amount of acompound of formula I.

Racemates of compounds of formula I wherein R₁ represents hydrogen andR₂ represents hydroxy or C₁-C₃alkyl carbonyloxy can, e.g., be obtainedby mixing the pure enantiomers of the respective compound of formula I.The pure enantiomers of a compound of formula I wherein R₁ representshydrogen and R₂ represents hydroxy or C₁-C₃alkyl carbonyloxy can beobtained starting from the racemate by procedures known as such. Theracemate may be separated into its enantiomers through the formation ofdiastereomeric salts, for example by salt formation with anenantiomer-pure chiral acid, or by means of chromatography, for exampleby HPLC, using chromatographic substrates with chiral ligands.

In one embodiment of the invention, the pure enantiomers of the compoundof formula I wherein R₁ represents hydrogen and R₂ represents hydroxyare prepared according to the procedures described in the Examples.

The pure enantiomers of the compound of formula I wherein R₁ representshydrogen and R₂ represents C₁-C₃alkyl carbonyloxy can be prepared, e.g.,according to the procedures described in U.S. Pat. No. 5,753,646 orWO02/09257.

The term “enantiomerically pure form” as used herein means that a chiralcompound is almost free of its enantiomer, i.e., a sample of the chiralcompound comprises less than about 5, preferably less than about 2, morepreferably less than about 0.5, weight percent of its enantiomer.

Hence, the present invention relates to the use of a compound of formulaI, wherein R₁ represents hydrogen and R₂ represents hydroxy orC₁-C₃alkyl carbonyloxy, especially acetoxy, wherein the compound isemployed in enantiomerically pure form, in particular of a compound offormula I having the S configuration.

The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

Abbreviations Ac acetyl aqu. aqueous dansyl5-(dimethylamino)-1-naphthalenesulfonyl Et ethyl HPLC high pressureliquid chromatography Me methyl NMR nuclear magnetic resonance RT roomtemperature THF tetrahydrofuran Ts tosyl

EXAMPLES Example 1 Procedure for the enantioselective TransferHydrogenation of 10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide toR(−)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide

To a mixture of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide (300 mg, 1.189 mmol) andRuCl[(1R,2R)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene, Aldrich,Switzerland) (8.8 mg, 0.0138 mmol) in CH₂Cl₂ (15 ml) is added dropwise apremixed solution of formic acid and NEt3 (5:2, 328 mg:289 mg) at 23° C.and stirred for 10 min. The clear solution is heated to reflux for 16 h.The reaction mixture is cooled to RT, diluted with CH₂Cl₂ (20 ml) andneutralised with aqu. NaHCO₃. After washing with brine the solution isconcentrated under reduced pressure. The residue is purified by flashchromatography on silica gel using a 6:1 EtOAc-MeOH mixture as eluent toafford ofR(−)-10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5-carboxamide(enantiomeric purity (ee)>99% determined by HPLC on Chiracel OD,Retention time: 9.46 min. [α]_(D) ^(rt)=−195.3° (ethanol). ¹H-NMR (400MHz, CDCl₃):7.70-7.20 (m, 8H), 5.30 (br s, 1H), 5.10-4.60 (br s, 2H),3.75-3.40 (m, 1H), 3.20-2.90 (m, 1H), 2.50 (br s, 2H). NMR-Datas referto Lit.: Benes, J et al., J. Med. Chem. 1999, 42, 2582-2587. Molecularweight: 254.291

Example 2 Procedure for the Enantioselective Transfer Hydrogenation of10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide toS(+)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide

To a mixture of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide (300 mg, 1.189 mmol) andRuCl[(1S,2S)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene) (11 mg, 0.0173 mmol)in CH₂Cl₂ (15 ml) is added in two portions a premixed solution of formicacid and NEt₃ (5:2, 656 mg:578 mg) at 23° C. and stirred for 10 min.After that formic acid is added (50 μl) and the clear solution is heatedto reflux for 16 h. The reaction mixture is cooled to RT, diluted withCH₂Cl₂ (20 ml) and neutralised with aqu. NaHCO₃. After washing withbrine the solution is concentrated under reduced pressure. The residueis purified by flash chromatography on silica gel using a 6:1 EtOAc-MeOHmixture as eluent to afford ofS(+)-10,11dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5carboxamide (ee>99%by HPLC on Chiracel OD). Retention time: 12.00 min. [α]_(D)^(rt)=+196.6° (ethanol). ¹H-NMR (400 MHz, CDCl₃):7.70-7.20 (m, 8H), 5.30(br s, 1H), 5.10-4.60 (br s, 2H), 3.75-3.40 (m, 1H), 3.20-2.90 (m, 1H),2.50 (br s, 2H). NMR-Datas refer to Lit.: Benes, J et al., J. Med. Chem.1999, 42, 2582-2587. Molecular weight: 254.291

Alternative production: To a mixture of10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide (300mg, 1.189 mmol) and RuCl[(1S,2S)-p-dansyl-NCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene) (8.5 mg, 0.012 mmol)in CH₂Cl₂ (15 ml) is added dropwise a premixed solution of formic acidand NEt3 (5:2, 328 mg:289 mg) at 23° C. and stirred for 10 min. Theclear solution is heated to reflux for 16 h. The reaction mixture iscooled to RT, diluted with CH₂Cl₂ (20 ml) and neutralised with aqu.NaHCO₃. After washing with brine the solution is concentrated underreduced pressure. The residue is purified by flash chromatography onsilica gel using a 6:1 EtOAc-MeOH mixture as eluent to afford ofS(+)-10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5-carboxamide.

Example 3 Preparation ofRuCl[(1S,2S)-p-dansylNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene)

-   a) Preparation of (S,S)-5-dimethylamino-naphthalene-1-sulfonic acid    (2-amino-1,2-diphenyl-ethyl)-amide: To a solution of    (S,S)-diphenylethylenediamine (250 mg, 1.2 mmol) and triethylamine    (0.5 ml) in THF is added dropwise a solution of dansyl chloride (318    mg, 1.2 mmol) in THF (2 ml) at 0° C. After stirring 16 h at RT the    solvent is removed in vacuum and the residue is resolved in    methylenchloride (20 ml). The organic solution is washed with NaHCO₃    solution (5 ml), dried over Na₂SO₄ and after filtration the solvent    is removed. Flash chromatographie afford    (S,S)-5-dimethylamino-naphthalene-1-sulfonic acid    (2-amino-1,2-diphenyl-ethyl)-amide as yellow oil which crystallizes    by drying in vacuum. M: 445.59. ¹H-NMR (400 MHz, CDCl₃):8.36 (t,    J=7.5 Hz, 2H), 8.17 (dd, J=7.2, 1.2 Hz, 1H), 7.47 (dd, J=8.8 Hz,    1H), 7.34 (dd, J=8.5 Hz, 1H), 7.24-7.16 (m, 4H), 7.11 (d, J=7.5 Hz,    1H), 6.99-6.74 (m, 6H), 4.61 (d, J=8.5 Hz, 1H), 4.20 (d, J=8.5 Hz,    1H), 2.80 (s, 6H).-   b) Preparation of    RuCl[(1S,2S)-p-dansylNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene): A solution    of (S,S)-5-dimethylamino-naphthalene-1-sulfonic acid    (2-amino-1,2-diphenyl-ethyl)-amide (80 mg, 0.18 mmol), NEt₃ (36 mg,    0.36 mmol) and [RuCl₂(p-cymene)]₂ (55 mg, 0.09 mmol) in 2-propanol    is heated at 80° C for 1 h. The solvent is removed after that und    the dark red residue is washed with water (2 ml). The solid is dried    in vacuum and used without any purification. M: 715.34.

1. A method of treatment for tinnitus in a subject in need of suchtreatment, which comprises administering to said subject atherapeutically effective amount of a compound of formula I

wherein (a) R₁ represents hydrogen, and R₂ represents hydroxy or C₁-C₃alkyl carbonyloxy, or (b) R₁ and R₂ together represent an oxo group, orpharmaceutically acceptable salt thereof.
 2. A method of treatmentaccording to claim 1 wherein R₁ and R₂ of formula I or pharmaceuticallyacceptable salt thereof together represent an oxo group.
 3. A method oftreatment according to claim 1 wherein R₁ of formula I orpharmaceutically acceptable salt thereof represent hydrogen and R₂represents hydroxy.
 4. A method of treatment according to claim 1wherein R₁ of formula I or pharmaceutically acceptable salt thereofrepresent hydrogen and R₂ represents acetoxy.
 5. A method of treatmentaccording to claim 1 wherein R₁ of formula I represents hydrogen and R₂represents hydroxy or C₁-C₃ alkyl carbonyloxy and wherein the compoundis employed in enantiomerically pure form.